Inhibition of S6K by resveratrol

Cross talk between two antioxidant systems, Thioredoxin and DJ-1: consequences for cancer ABSTRACT Oxidative stress, which is associated with an increased concentration of reactive oxygen species (ROS), is involved in the pathogenesis of numerous diseases including cancer. In response to increased ROS levels, cellular antioxidant molecules such as thioredoxin, peroxiredoxins, glutaredoxins, DJ-1, and superoxide dismutases are upregulated to counteract the detrimental effect of ROS. However, cancer cells take advantage of upregulated antioxidant molecules for protection against ROS-induced cell damage. This review focuses on two antioxidant systems, Thioredoxin and DJ-1, which are upregulated in many human cancer types, correlating with tumour proliferation, survival, and chemo-resistance. Thus, both of these antioxidant molecules serve as potential molecular targets to treat cancer. However, targeting one of these antioxidants alone may not be an effective anti-cancer therapy. Both of ...

Cigarette smoke-induced lung inflammation in COPD mediated via CCR1/JAK/STAT /NF-κB pathway Abstract Inflammation is an important cause of chronic obstructive pulmonary disease (COPD) and its acute exacerbation. However, the critical role of C-C chemokine receptor (CCR)1 in progression of cigarette smoke-induced chronic inflammation remains unclear. We studied CCR1 expression using immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction (RT-PCR) in COPD patients and controls. Cytokine levels in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, we investigated Janus kinase/signal transducers and activators of transcription (JAK/STAT)/nuclear factor-κB (NF-κB) signaling in cigarette smoke extract-induced or CCR1 deficiency/overexpressed mouse macrophage cell line MH-S by RT-PCR and western blot, and measured the cytokine levels in the supernatant with ELISA. We found that CCR1 expression was upregulated in COPD patients and t...

Construction of immune-related and prognostic lncRNA clusters and identification of their immune and genomic alterations characteristics in lung adenocarcinoma samples Abstract Long non-coding RNAs (lncRNAs) play an important role in various biological processes of lung adenocarcinoma (LUAD), such as immune response regulation, tumor microenvironment remodeling and genomic alteration. Nevertheless, immune-related lncRNAs and their immune and genomic alterations characteristics in LUAD samples still remain unreported. Here, using various public databases, statistic and software tools, we constructed two immune-related lncRNA clusters with different immune and genomic alterations characteristics. Notably, cluster 1 had a stronger immunosuppressive tumor microenvironment (TME) and a higher mutation frequency than cluster 2, especially the mutant genes, such as Kelch-like ECH-associated protein 1 (KEAP1) and toll like receptor 4 (TLR4). In cluster 1, both the amplified and deleted portions...

Dysregulation of antimicrobial peptide expression distinguishes Alzheimer’s disease from normal aging Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease with unknown mechanism that is characterized by the aggregation of abnormal proteins and dysfunction of immune responses. In this study, an integrative approach employing  in silico  analysis and wet-lab experiment was conducted to estimate the degrees of innate immune system relevant gene expression, neurotoxic Aβ 42  generation and neuronal apoptosis in normal  Drosophila melanogaster  and a transgenic model of AD. Results demonstrated mRNA levels of antimicrobial peptide (AMP) genes gradually increased with age in wild-type flies, while which exhibited a trend for an initial decrease followed by subsequent increase during aging in the AD group. Time series and correlation analysis illustrated indicated a potential relationship between variation in AMP expression and Aβ 42  conc...

Dual MTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) Abstract In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants i...

The mystery of the ketogenic diet: benevolent pseudo-diabetes ABSTRACT Designed a century ago to treat epilepsy, the ketogenic diet (KD) is also effective against obesity and diabetes. Paradoxically, some studies in rodents have found that the KD seemingly causes diabetes, contradicting solid clinical data in humans. This paradox can be resolved by applying the concept of starvation pseudo-diabetes, which was discovered in starved animals almost two centuries ago, and has also been observed in some rapamycin-treated rodents. Intriguingly, use of the KD and rapamycin is indicated for a similar spectrum of diseases, including Alzheimer’s disease and cancer. Even more intriguingly, benevolent (starvation) pseudo-diabetes may counteract type 2 diabetes or its complications. Iroduction A number of publications have alarmingly warned that the ketogenic diet (KD), or low carbohydrate-high fat (LC-HF) diet, may have detrimental metabolic effects that lead to the development of diabetes. For ex...

Raf-1/bcl-2 phosphorylation: A step from microtubule damage to cell death MeSH Major Antineoplastic Agents, Phytogenic Microtubules Paclitaxel Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Tubulin abstract Recent studies have shown that paclitaxel leads to activation of Raf-1 kinase and have suggested that this activation is essential for bcl-2 phosphorylation and apoptosis. In the present study, we demonstrate that, in addition to paclitaxel, other agents that interact with tubulin and microtubules also induce Raf-1/bcl-2 phosphorylation, whereas DNA-damaging drugs, antimetabolites, and alkylating agents do not. Activation of Raf-1 kinase by paclitaxel is linked to tubulin polymerization; the effect is blunted in paclitaxel-resistant cells, the tubulin of which does not polymerize following the addition of paclitaxel. In contrast, vincristine and vinblastine, drugs to which the paclitaxel-resistant cells retain sensitivity were able to bring ...

Mikhail Blagosklonny Email: blagosklonny@oncotarget.com Also known as: M V Blagosklonny WormBase ID: WBPerson13747 Department of Cell Stress Biology Roswell Park Cancer Institute BLSC, L3-312 Elm and Carlton Streets Buffalo, NY 14263 Institution:  Roswell Park Cancer Institute; Buffalo NY, United States of America https://wormbase.org/resources/person/WBPerson13747#10--10 When people mention contemporary medicine, accuracy plays one of the most significant roles and human lives are literally dependent on it. Hence, any researches related to medicine are required to comply with the highest standards. The challenge today is that any results of researches can be published online and used as a reference without being adequately verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this issue and decided to come up with an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been established back in 2010. Th...

Rapamycin for longevity: opinion article Mikhail V. Blagosklonny https://doi.org/10.18632/aging.102355 How to Cite Abstract From the dawn of civilization, humanity has dreamed of immortality. So why didn’t the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its...